RESUMEN
A series of potent 2-carboxychromone-based melanin-concentrating hormone receptor 1 (MCHr1) antagonists were synthesized and evaluated for hERG (human Ether-a-go-go Related Gene) channel affinity and functional blockade. Basic dialkylamine-terminated analogs were found to weakly bind the hERG channel and provided marked improvement in a functional patch-clamp assay versus previously reported antagonists of the series.
Asunto(s)
Amidas/farmacología , Cromonas/farmacología , Canales de Potasio Éter-A-Go-Go/metabolismo , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Animales , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Ratones , Obesidad/tratamiento farmacológico , Técnicas de Placa-Clamp , FarmacocinéticaRESUMEN
The optimization of potent MCHr1 antagonist 1 with respect to improving its in vitro profile by replacement of the 3,4-methylenedioxy phenyl (piperonyl) moiety led to the discovery of 19, a compound that showed excellent MCHr1 binding and functional potencies in addition to possessing superior hERG separation, CYP3A4 profile, and receptor cross-reactivity profiles.
Asunto(s)
Piperidinas/síntesis química , Piperidinas/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Alquilación , Animales , Fenómenos Químicos , Química Física , Cromonas , Reacciones Cruzadas , Citocromo P-450 CYP3A , Inhibidores Enzimáticos del Citocromo P-450 , Relación Dosis-Respuesta a Droga , Canal de Potasio ERG1 , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Canales de Potasio Éter-A-Go-Go/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Humanos , Ratones , Relación Estructura-ActividadRESUMEN
The incorporation of constrained tertiary amines into an existing class of N-benzyl-4-aminopiperidinyl chromone-based MCHr1 antagonists led to the identification of a series of chiral racemic compounds that displayed good to excellent functional potency, binding affinity, and selectivity over the hERG channel. Further separation of two distinct chiral racemic compounds into their corresponding pairs of enantiomers revealed a considerable selectivity for MCHr1 for one configuration, in addition to a striking difference in oral exposure between one pair of enantiomers in diet-induced obese mice. Oral administration of the most potent compound in this class in the same animal model led to significant reduction of fat mass in a semi-chronic model for weight loss.
Asunto(s)
Cromonas/síntesis química , Cromonas/farmacología , Piperidinas/síntesis química , Piperidinas/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacología , Depresores del Apetito/farmacología , Peso Corporal/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular , Dieta , Grasas de la Dieta , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Fenfluramina/farmacología , Indicadores y Reactivos , Ratones , Conformación Molecular , Bloqueadores de los Canales de Potasio/síntesis química , Bloqueadores de los Canales de Potasio/farmacología , Relación Estructura-ActividadRESUMEN
Evaluation of multiple structurally distinct series of melanin concentrating hormone receptor 1 antagonists in an anesthetized rat cardiovascualar assay led to the identification of a chromone-2-carboxamide series as having excellent safety against the chosen cardiovascular endpoints at high drug concentrations in the plasma and brain. Optimization of this series led to considerable improvements in affinity, functional potency, and pharmacokinetic profile. This led to the identification of a 7-fluorochromone-2-carboxamide (22) that was orally efficacious in a diet-induced obese mouse model, retained a favorable cardiovascular profile in rat, and demonstrated dramatic improvement in effects on mean arterial pressure in our dog cardiovascular model compared to other series reported by our group. However, this analogue also led to prolongation of the QT interval in the dog that was linked to affinity for hERG channel and unexpectedly potent functional blockade of this ion channel.
Asunto(s)
Benzodioxoles/farmacología , Enfermedades Cardiovasculares/inducido químicamente , Cromonas/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Acilación , Animales , Área Bajo la Curva , Benzodioxoles/farmacocinética , Benzodioxoles/toxicidad , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Calcio/metabolismo , Línea Celular , Cromonas/farmacocinética , Cromonas/toxicidad , Perros , Electrocardiografía/efectos de los fármacos , Femenino , Semivida , Frecuencia Cardíaca/efectos de los fármacos , Indicadores y Reactivos , Ratones , Ratones Endogámicos C57BL , Canales de Potasio/efectos de los fármacos , Canales de Potasio/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
An inactin-anesthetized rat cardiovascular (CV) assay was employed in a screening mode to triage multiple classes of melanin-concentrating hormone receptor 1 (MCHr1) antagonists. Lead identification was based on a compound profile producing high drug concentration in both plasma (>40 microM) and brain (>20 microg/g) with <15% change in cardiovascular endpoints. As a result of these stringent requirements, lead optimization activities on multiple classes of MCHr1 antagonists were terminated. After providing evidence that the cardiovascular liabilities were not a function of MCHr1 antagonism, continued screening identified the chromone-substituted aminopiperidine amides as a class of MCHr1 antagonists that demonstrated a safe cardiovascular profile at high drug concentrations in both plasma and brain. The high incidence of adverse cardiovascular effects associated with an array of MCHr1 antagonists of significant chemical diversity, combined with the stringent safety requirements for antiobesity drugs, highlight the importance of incorporating cardiovascular safety assessment early in the lead selection process.
Asunto(s)
Fármacos Antiobesidad/síntesis química , Sistema Cardiovascular/efectos de los fármacos , Cromonas/síntesis química , Piperidinas/síntesis química , Receptores de Somatostatina/antagonistas & inhibidores , Animales , Fármacos Antiobesidad/efectos adversos , Fármacos Antiobesidad/sangre , Presión Sanguínea/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular Tumoral , Cromonas/efectos adversos , Cromonas/sangre , Perros , Indazoles/efectos adversos , Indazoles/sangre , Indazoles/síntesis química , Masculino , Ratones , Ratones Endogámicos C57BL , Contracción Miocárdica/efectos de los fármacos , Piperidinas/efectos adversos , Piperidinas/sangre , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Distribución TisularRESUMEN
The synthesis and biological evaluation of novel 3-amino indazole melanin concentrating hormone receptor-1 antagonists are reported, several of which demonstrated functional activity of less than 100nM. Compounds 19 and 28, two of the more potent compounds identified in this study, were characterized by high exposure in the brain and demonstrated robust efficacy when dosed in diet-induced obese mice.